To date, there has been no information about the long-term replication mechanisms of the beta papillomaviruses. We have found that the beta HPV E2 proteins (HPV 5 and 8) associate with the peri-centromeric region of mitotic chromosomes and interact with the repeated ribosomal DNA genes found in this location. We have found that the domains of HPV8 E2 required for chromosomal association are also quite different from other papillomavirus E2 proteins, further supporting the finding that these proteins have different targets. We have mapped a short 16 amino acid peptide from the hinge region of E2 that is necessary and for interaction with mitotic chromosomes. This 16 amino acid region contains an RXXS motif that is highly conserved among beta-papillomaviruses. The HPV8 E2 chromosome binding sequence also has sequence similarity with chromosome binding regions in the gamma herpesvirus EBNA and LANA tethering proteins. We have shown that this motif is phosphorylated by protein kinase A and phosphorylation modulates the association of E2 with host chromatin.